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1.  Global assessment of genetic variation influencing response to retinoid chemoprevention in head and neck cancer patients 
Head and neck squamous cell carcinoma (HNSCC) patients are at an increased risk of developing a second primary tumor (SPT) or recurrence following curative treatment. 13-cis-retinoic acid (13-cRA) has been tested in chemoprevention clinical trials but the results have been inconclusive. We genotyped 9,465 SNPs in 450 patients from the Retinoid Head and Neck Second Primary Trial. SNPs were analyzed for associations with SPT/recurrence in patients receiving placebo to identify prognosis markers and further analyzed for effects of 13-cRA in patients with these prognostic loci. Thirteen loci identified a majority subgroup of patients at a high risk of SPT/recurrence and in whom 13-cRA was protective. Patients carrying the common genotype of rs3118570 in the retinoid X receptor (RXRA) were at a 3.33-fold increased risk (95% confidence interval [CI], 1.67–6.67) and represented over 70% of the study population. This locus also identified individuals who received benefit from chemoprevention with a 38% reduced risk (95% CI, 0.43–0.90). Analyses of cumulative effect and potential gene-gene interactions also implicated CDC25C:rs6596428 and JAK2:rs1887427 as two other genetic loci with major roles in prognosis and 13-cRA response. Patients with all three common genotypes had a 76% reduction in SPT/recurrence (95% CI, 0.093–0.64) following 13-cRA chemoprevention. Carriers of these common genotypes constituted a substantial percentage of the study population, indicating that a pharmacogenetics approach could help select patients for 13-cRA chemoprevention. The lack of any alternatives for reducing risk in these patients highlights the need for future clinical trials to prospectively validate our findings.
PMCID: PMC3955084  PMID: 21292633
HNSCC; SPT; single nucleotide polymorphisms; retinoids
2.  Genetic variants in the PI3K/PTEN/AKT/MTOR pathway predict head and neck cancer patient second primary tumor/recurrence risk and response to retinoid chemoprevention 
Clinical Cancer Research  2012;18(13):3705-3713.
The development of second primary tumors (SPT) or recurrence alters prognosis for curatively-treated head and neck squamous cell carcinoma (HNSCC) patients. 13-cis-retnoic acid (13-cRA) has been tested as a chemoprevention agent in clinical trials with mixed results. Therefore, we investigated if genetic variants in the PI3K/PTEN/AKT/MTOR pathway could serve as biomarkers to identify which patients are at high risk of an SPT/recurrence while also predicting response to 13-cRA chemoprevention.
Experimental Design
A total of 137 pathway SNPs were genotyped in 440 patients from the Retinoid Head and Neck Second Primary Trial and assessed for SPT/recurrence risk and response to 13-cRA. Risk models were created based on epidemiology, clinical, and genetic data.
Twenty-two genetic loci were associated with increased SPT/recurrence risk with six also being associated with a significant benefit following chemoprevention. Combined analysis of these high-risk/high-benefit loci identified a significant (P = 1.54×10−4) dose-response relationship for SPT/recurrence risk, with patients carrying 4–5 high-risk genotypes having a 3.76-fold (95%CI:1.87–7.57) increase in risk in the placebo group (n=215). Patients carrying 4–5 high-risk loci showed the most benefit from 13-cRA chemoprevention with a 73% reduction in SPT/recurrence (95%CI:0.13–0.58) compared to those with the same number of high-risk genotypes who were randomized to receive placebo. Incorporation of these loci into a risk model significantly improved the discriminatory ability over models with epidemiology, clinical, and previously identified genetic variables.
These results demonstrate that loci within this important pathway could identify individuals with a high-risk/high-benefit profile and are a step towards personalized chemoprevention for HNSCC patients.
PMCID: PMC3404728  PMID: 22577058
3.  Novel Susceptibility Loci for Second Primary Tumors/Recurrence in Head and Neck Cancer Patients: Large Scale Evaluation of Genetic Variants 
This study was aimed to identify novel susceptibility variants for second primary tumor (SPT) or recurrence in curatively treated early stage head and neck squamous cell carcinoma (HNSCC) patients.
We constructed a custom chip containing a comprehensive panel of 9645 chromosomal and mitochondrial single nucleotide polymorphisms (SNPs) representing 998 cancer-related genes selected by a systematic prioritization schema. Using this chip, we genotyped 150 early-stage HNSCC patients with and 300 matched patients without SPT/recurrence from a prospectively conducted randomized trial and assessed the association of these SNPs with risk of SPT/recurrence.
Individually, six chromosomal SNPs and seven mitochondrial SNPs (mtSNPs) were significantly associated with risk of SPT/recurrence after adjustment for multiple comparisons. A strong gene-dosage effect was observed these SNPs were combined, as evidenced by a progressively increasing SPT/recurrence risk as the number of unfavorable genotypes increased (P for trend < 1.00×10−20). Several polygenic analyses suggest an important role of interconnected functional network and gene-gene interaction in modulating SPT/recurrence. Furthermore, incorporation of these genetic markers into a multivariate model improved significantly the discriminatory ability over the models containing only clinical and epidemiologic variables.
This is the first large scale systematic evaluation of germline genetic variants for their roles in HNSCC SPT/recurrence. The study identified several promising susceptibility loci and demonstrated the cumulative effect of multiple risk loci in HNSCC SPT/recurrence. Furthermore, this study underscores the importance of incorporating germline genetic variation data with clinical and risk factor data in constructing prediction models for clinical outcomes.
PMCID: PMC2964280  PMID: 19584075
iSelect Infinium; Single nucleotide polymorphisms; Head and neck cancer; Secondary primary tumor; recurrence
4.  Genetic Variations in Cell Cycle Pathway and the Risk of Oral Premalignant Lesions 
Cancer  2008;113(9):2488-2495.
Cell-cycle checkpoint regulates cell cycle progression and proliferation. Alterations in cell-cycle control mechanisms are linked to tumorigenesis.
This case-control study included 147 cases and 147 controls. We used a pathway-based approach to assess the association between 10 potential functional single-nucleotide polymorphisms from seven cell-cycle control genes and the risk of oral premalignant lesions (OPLs). We also used classification and regression tree analysis to examine high-order gene-gene and gene-smoking interactions.
Compared with the homozygous wild-type GG genotype of CCND1 P241P, individuals with the AG genotype exhibited an increased risk of OPL (odds ratio, 1.58; 95% confidence interval, 0.89–2.83), and carriers of the AA genotype had a significantly increased risk of OPL (odds ratio, 2.75; 95% confidence interval, 1.33–5.71), with risk increasing significantly with the increasing number of variant alleles (P = 0.006). The risk of OPL increased significantly as the number of unfavorable genotypes in the pathway increased (P = 0.002). The final decision tree in the CART analysis contained five terminal nodes. Compared with the never smokers (the lowest risk group), the odds ratios for terminal nodes 2 through 5 ranged from 1.21 to 5.40.
Our results illustrated the advantage of using a pathway-based approach for analyzing gene-gene and gene-smoking interactions. Specifically, we showed that genetic polymorphisms in cell-cycle control pathway genes may contribute to the risk of OPL.
PMCID: PMC2577230  PMID: 18823025
Cell-cycle pathway; SNP; Oral premalignant lesion; CART
5.  Genetic Polymorphisms in Double-Strand Break DNA Repair Genes Associate with Risk of Oral Premalignant Lesions 
Oral premalignant lesions (OPLs) are early genetic events en route to oral cancer. To identify individuals susceptible to OPL is critical to the prevention of oral cancer. In a case-control study consisting of 147 patients with histologically confirmed OPL and 147 matched controls, we evaluated the associations of 10 genetic variants in nine genes of the double-strand break (DSB) DNA repair pathway with OPL risk. The most notable finding was an intronic polymorphism (A17893G) of the XRCC3 gene. Compared with the homozygous wild-type AA genotype, the odds ratios [OR] (95% confidence interval [CI]) for the heterozygous AG and homozygous variant GG genotype were 0.85 (0.49–1.48) and 0.18 (0.07–0.47), respectively (P for trend=0.002). In addition, compared with the most common A-C haplotype of XRCC3 (in the order of A17893G-T241M), the G-C haplotype was associated with a significantly decreased risk of OPL (OR=0.40, 95% CI 0.23–0.68). Moreover, compared with individuals without the G-C haplotype, the ORs were 1.04 (0.56–1.95) and 0.20 (0.08–0.51) for subjects with one copy and two copies of the G-C haplotype, respectively (P for trend=0.005). Classification and regression tree (CART) analysis further revealed potential high-order gene-gene and gene-environmental interactions and categorized subjects into different risk groups according to their specific polymorphic signatures. Overall, our study provides the first epidemiological evidence supporting a connection between DSB gene variants and OPL development. Our data also suggest that the effects of high-order interactions should be taken into consideration when evaluating OPL predisposition.
PMCID: PMC2603619  PMID: 18579371
Double-strand break; Polymorphism; Haplotype; Oral premalignant lesion

Results 1-5 (5)